Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@:9]1([C:36]([F:39])([F:38])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][NH2:35])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45].[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C@@:9]1([C:36]([F:38])([F:39])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][N:35]2[CH2:41][CH2:42][CH2:43][S:44]2(=[O:46])=[O:45])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 50 °C
Yield: 64.2 %

Procedure:
A solution of ((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methanamine (34, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rg=Benzyl) (82 mg, 0.153 mmol) in DCM (3 mL) was treated with TEA (0.021 mL, 0.153 mmol) and 3-chloro-propane-1-sulfonyl chloride (0.023 mL, 0.19 mmol) at rt under nitrogen for about 1 h. The organic layer was washed with 2N aq. HCl (2 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and added dropwise to a suspension of sodium hydride (60 wt % in oil, 7.6 mg, 0.30 mmol) in DMF (1 mL). The reaction was heated at about 50° C. for 2 h and then cooled to rt and concentrate under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-30% EtOAc in DCM. Product fractions were combined and concentrated to yield 2-(((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)isothiazolidine 1,1-dioxide (35, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rg=Benzyl) (63 mg, 64%) as an oil. LC/MS, method 3, Rt=3.01 min, MS m/z 642 (M+H)+. The oil was used in step #2 without further purification.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]1[C:9]2=[C:10]([S:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:11]3[C:12]([CH:25]([CH3:27])[CH3:26])=[CH:13][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.CC(O)=O>C1COCC1.CO.[Li+].[OH-]>[CH2:18]([O:17][C:14]1[CH:13]=[C:12]([CH:25]([CH3:27])[CH3:26])[C:11]2[C:10]([S:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[C:9]3[CH:5]([CH2:4][C:3]([OH:36])=[O:2])[CH2:6][CH2:7][N:8]3[C:16]=2[CH:15]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(C)C)cc(OCc3ccccc3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(OCc2ccccc2)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of the ester of Step 5 100 mg in THF/MeOH (3/1) mixture at r.t. was added in LiOH aqueous solution 1.0 mL. The reaction mixture was stirred at r.t. for 1 hour then AcOH was added and the solvent was evaporated. The residue was taken up in EtOAc/H2O and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by silica gel chromatography, eluting with 1% AcOH in EtOAc to give 70 mg of the title compound.
Reaction SMILES: [N:1]([C@H:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6])=[N+]=[N-].[ClH:23].[H][H]>O1CCCC1.O.[Pd]>[ClH:23].[NH2:1][C@H:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: [N-]=[N+]=N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21

Procedure:
To a solution of (R)-α-azido-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid (3.5 g, 1.9 mmol) in tetrahydrofuran (75 mL), water (10 mL), and concentrated hydrochloric acid (1 mL) is added palladium on carbon (0.5 g, 20%). The mixture is shaken under 52 pounds per square inch (psi) of hydrogen at 25° C. for 6 hours. Solid is filtered. The filtrate is concentrated in vacuo to give a light green solid, which is recrystallized in 3N hydrochloric acid (with activated charcoal) to give the title compound as a white solid, 2.84 g; mp 313°-314° C. (dec), [α]D =47.6° (c=1.0, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[N:21]=[CH:20][C:19](C#N)=[CH:18][C:17]=4[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[CH3:30][Li].Cl.[C:33](=[O:36])(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[N:21]=[CH:20][C:19]([C:33](=[O:36])[CH3:30])=[CH:18][C:17]=4[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: [Li]C
Reactant: O=C([O-])O
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(C#N)cc1C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(C(C)=O)cc1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A mixture of 6-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-5-methylpyridine-3-carbonitrile (90 mg, 0.22 mmol) in tetrahydrofuran (2 mL) was added methyllithium (1.8 M solution in ether, 0.61 mL, 1.10 mmol) at −78° C. After stirring for 1 hr at −78° C., 1 N hydrochloric acid was added and the mixture was warmed to room temperature during 15 min. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/n-hexane to afford the title compound (70 mg, 67%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:19][C:20]([N:22]([CH2:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])[C:5](=[O:18])[N:6]2[CH3:17].Cl.[CH3:32][NH:33][CH3:34].C(N(CC)CC)C>CN(C)C=O>[CH2:29]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](=[O:21])[CH2:19][N:4]1[C:3]2[C:7](=[N:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:2]=2[N:33]([CH3:34])[CH3:32])[N:6]([CH3:17])[C:5]1=[O:18])[CH3:30]
Reactant: CNC
Reactant: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(Cl)c21)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(N(C)C)c21)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
A mixture of 6-chloro-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide obtained in Example 45 (0.6 g), dimethylamine hydrochloride (0.2 g), triethylamine (0.4 g) and dimethylformamide (20 ml) is stirred at 100° C. for four hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added water and chloroform. The chloroform layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from diisopropyl ether to give the desired compound (0.34 g).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]#[N:21])=[CH:17][CH:18]=3)[C:13]([CH3:22])=[C:12]2[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1.[OH-].[Li+]>CO.C1COCC1>[C:20]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=1)[C:12]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[C:13]2[CH3:22])#[N:21]
Reactant: COC(=O)c1ccc(Cn2c(-c3cccnc3)c(C)c3cc(C#N)ccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C(=O)O)cc2)c2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Cyano-3-methyl-2-pyridin-3-yl-indole (Example 6) is processed according to the method described in Example 11 to give 4-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid methyl ester. To a solution of 4-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid methyl ester (80 mg, 0.21 mmol) in methanol (5 mL) and THF (5 mL) is added 1M aqueous lithium hydroxide (2.5 mL, 2.5 mmol) and the mixture is stirred overnight at ambient temperature. The volatiles are removed in vacuo and the residue is redissolved in DMF and purified by Xbridge RP18 with a gradient of 0.1% aqueous ammonium hydroxide in acetonitrile to give 4-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H), 5.40 (s, 2H), 6.71 (d, J=8.1 Hz, 2H), 7.47-7.55 (m, 2H), 7.66 (t, J=8.6 Hz, 3H), 7.79-7.83 (m, 1H), 8.20 (d, J=1.3 Hz, 1H), 8.58 (d, J=1.5 Hz, 1H), 8.64 (dd, J=4.8, 1.5 Hz, 1H). HRMS (ESI) m/z 368.1396 [(M+H)+ Calcd for C23H18N3O2: 368.1399].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].[N+:11]([O-])([OH:13])=[O:12]>S([O-])([O-])(=O)=O.[Ni+].[NH4+].ClCCl>[Br:1][C:2]1[C:3]([OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(F)c(F)cc1Br
Agent: [Ni+]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=[N+]([O-])c1c(O)c(Br)cc(F)c1F
Reaction time: 0.42 h

Procedure:
To a round bottom flask containing 2-bromo-4,5-difluorophenol (2.7 g, 12.9 mmol) and ammonium nickel sulfate (2.6 g, 6.46 mmol) is added dichloromethane (15 mL) at RT. A solution of 70% nitric acid (1.2 ml) is added dropwise and the slurry is stirred for 20 to 30 min. The mixture is then quenched with excess MgSO4, filtered and concentrated. The product is used in the next step without purification.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][O:11][CH3:12].Cl[CH2:14][C:15]1[N:16]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:27])[C:18]=2[N:28]=1.O>CN(C=O)C>[OH:33][C:30]([CH3:32])([CH3:31])[CH2:29][N:16]1[C:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:27])[C:18]=2[N:28]=[C:15]1[CH2:14][N:10]([O:11][CH3:12])[CH3:9]
Reactant: CC(C)(O)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Reactant: CNOC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 50 °C
Reaction time: 17 h
Yield: 16.3 %

Procedure:
Triethylamine (0.747 g, 1.03 mL, 7.38 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.480 g, 4.92 mmol) were added to a stirring suspension of 2-chloromethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.750 g, 2.46 mmol) in DMF (5 mL). The resulting suspension was heated to 50° C. and stirred for 17 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). A solid was removed by filtration and discarded. The filtrate was extracted with ethyl acetate (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 5-20% methanol in dichloromethane). The resulting oil was crystallized from dichloromethane and isolated by filtration to yield 132 mg of 1-(2-Hydroxy-2-methylpropyl)-2-{[methoxy(methyl)amino]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 220-222° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([O-:5])=O.C(O[C:11]([C:13]1[NH+:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH2:15][CH2:16][N:17]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:18]2=[O:24])=O)C.Br[N:34]1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:13]([N:22]1[CH2:21][C:20]([OH:23])=[C:19]2[C:14]([CH:15]=[CH:16][N:17]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:18]2=[O:24])=[C:2]1[C:3]([NH2:34])=[O:5])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1[nH+]cc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Reactant: O=C([O-])C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCN1CC(O)=c2c(ccn(Cc3ccc(F)cc3)c2=O)=C1C(N)=O
Temperature: 80 °C

Procedure:
To solution of 5-(ethoxycarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydro-2,6-naphthyridin-6-ium trifluoroacetate (0.020 g, 0.045 mmol; see Example 8, Step 4) in CCl4 (2 mL) is added N-bromo succinimide (0.017 g, 0.095 mmol) and AIBN (catalytic). The reaction is heated to 80° C. for 1 hour, then concentrated and chromatographed on reverse phase to give the product.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1.Cl.[CH2:33]([NH2:35])[CH3:34].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl.C(Cl)(Cl)Cl>[CH2:33]([NH:35][C:28]([C:26]1[N:27]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:31]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:18]=2)[O:24][CH:25]=1)=[O:29])[CH3:34]
Reactant: CCN
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C(=O)O)co3)c1)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)c1coc(-c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.7 %

Procedure:
(S)-2-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxylic acid (105 mg, 0.240 mmol) obtained in Step 1 was dissolved in dichloromethane (5 mL), and the mixture was stirred at room temperature for 5 hours after adding ethylamine hydrochloride (39.0 mg, 0.480 mmol), triethylamine (0.067 mL, 0.480 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (92.0 mg, 0.480 mmol), and 1-hydroxybenzotriazole.monohydrate (37.0 mg, 0.240 mmol). The mixture was diluted with chloroform and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)—N-ethyl 2-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxamide (110 mg, quantitative).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1I>CCCCCC.O1CCCC1.CCOCC.[Cl-].[Zn+2].[Cl-]>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:18]2[C:17]([C:16]([O:15][CH3:14])=[O:24])=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccccc1I
Reactant: Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
A 1.6M solution of butyllithium in hexane (24.0 ml) was added dropwise to a stirred solution of 4-bromotoluene (6.0 g) in dry tetrahydrofuran (THF) (50 ml) at -78° C. under an atmosphere of argon. The temperature was maintained at -78° C. for 20 minutes and then a 1M solution of anhydrous zinc chloride in ether (38.6 ml) was added. The solution was kept at -78° C. for 15 minutes, and then tetrakis (triphenylphosphine)palladium (60 mg) in THF (5 ml) was added, followed by methyl-2-iodobenzoate (6.1 g) in THF (10 ml). The solution was allowed to reach ambient temperature over 1 hour, then heated under reflux for 5 hours. The solvent was removed by evaporation and the residue was dissolved in chloroform (150 ml). The solution was washed with a solution of ethylene diaminetetracetic acid (10 g) in water (100 ml) and the aqueous layer was re-extracted with chloroform (100 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v) to give methyl 4'-methylbiphenyl-2-carboxylate (B) as a colourless oil (4.4 g); NMR: 2.4(s,3H), 3.65(s,3H), 7.2(s,4H), 7.35(m,3H), 7.5(m,1H), 7.8(d,1H).
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7]Cl)(=[O:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].O>CN(C)C=O>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7][N:30]=[N+:31]=[N-:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCCl)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CCCN=[N+]=[N-])c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 70 °C
Reaction time: 4 h
Yield: 105.6 %

Procedure:
810 mg (1.91 mmol) of 2-[4-[N-acetyl-N-(3-chloropropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 50 was dissolved in 40 ml of dimethylformamide under argon atmosphere, 622 mg of sodium azide was added at room temperature and the mixture was stirred at 70° C. for 4 hours. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, the organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 870 mg of 2-[4-[N-acetyl-N-(3-azidopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:17][C:18]1[CH:25]=[CH:24][C:21](NC)=[CH:20][CH:19]=1.[CH2:26]([N:28](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([NH:28][CH2:26][C:21]2[CH:20]=[CH:19][C:18]([Cl:17])=[CH:25][CH:24]=2)=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNc1ccc(Cl)cc1
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)NCc1ccc(Cl)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (10.0 g) in CH2Cl2 (150 mL) at 0° C. was treated sequentially with 4-chloro-N-methylaniline (6.8 g), triethylamine (4.87 g) and N,N-dimethylaminopyridine (0.5 g). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was washed with 1N HCl (3×100 mL) and water (100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (14.9 g).
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[Br:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Br
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Br
Temperature: 25 °C
Yield: 51.9 %

Procedure:
4-Bromo-2-fluoro-5-isopropoxyaniline (2.0 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.23 g) were dissolved in acetic acid (10 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 1.6 g of N-(4-bromo-2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (Compound No. 2). M.P., 116.5°-117.5° C.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:26][CH2:27][CH2:28]Cl)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[Na+].[I-].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(#N)C.O>[C:1]([NH:4][C:5]([CH2:26][CH2:27][CH2:28][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCCCl)(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)NC(C)(C)C
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(CCCN1CCCC1)C(=O)NC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-(3-chloropropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (0.39 g, 0.9 mmol) in acetonitrile was treated with NaI (10% mol) and pyrolidine (0.75 mL, 9 mmol). The mixture was warmed to 50° C. and stirred overnight. After cooling to room temperature, the reaction was diluted with water, extracted with dichloromethane, dried over MgSO4, and concentrated to give crude 2-acetamido-N-tert-butyl-2-(3-(pyrrolidin-1-yl)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (0.31 g). This material was used in the next step without further purification. ESI MS found for C25H48BN3O4 m/z [466.6 (M+1)].
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>C(O)C>[ClH:13].[N+:20]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCOC(=O)c1ccccc1N
Solvent: CCO
Product: CCOC(=O)c1ccccc1Nc1ccncc1[N+](=O)[O-]
Product: Cl

Procedure:
A solution of ethyl 2-aminobenzoate (3.17 g, 20 mmol) and 4-chloro-3-nitropyridine (2.8 ml) in ethanol (150 ml) was stirred at room temperature for 60 hours. The resulting precipitate was collected, washed with ethanol and dried to give ethyl 2-(3-nitro-4-pyridylamino)benzoate hydrochloride (3.9 g) as a yellow crystalline solid, m.p. 192°-205° C.